Search Results (14,525)

Managing blood glucose in type 1 diabetes (T1D) remains a daily clinical challenge, and accurate short-term prediction of glucose levels can meaningfully improve insulin dosing decisions while reducing the risk of dangerous hypoglycaemic episodes. Although numerous machine learning approaches have been proposed for this task, comparing their relative merits is difficult because published studies differ widely in datasets, preprocessing choices, and evaluation criteria. In this work, we address this research gap by benchmarking ten machine learning methods—from a naïve persistence baseline through classical linear regressors, gradient-boosted ensembles, and recurrent neural networks to a novel hybrid that couples LightGBM with stochastic differential equation (SDE)-based glucose–insulin simulation—on two multi-patient datasets comprising 34 T1D subjects, across prediction horizons of 15, 30, 60, and 120 min. Every method is trained and tested under identical preprocessing and temporal splitting conditions to ensure a fair comparison. The proposed Hybrid LightGBM-SDE model consistently outperforms all alternatives, recording RMSE values of 22.42 mg/dL at 15 min, 28.74 mg/dL at 30 min, 33.89 mg/dL at 60 min, and 37.22 mg/dL at 120 min—an improvement of between 13.6% and 27.0% relative to standalone LightGBM. At the clinically important 30 min horizon, 99.7% of predictions lie within the acceptable A and B zones of the Clarke Error Grid. Wilcoxon signed-rank tests confirm that performance differences are statistically significant (p < 10⁻¹⁰), and SHAP-based analysis shows that the SDE-derived simulation features are among the most influential predictors, especially at longer horizons. All source code and evaluation scripts are publicly released to support reproducibility. Due to temporary data access constraints, all experiments reported here use physics-based synthetic datasets generated from the Bergman minimal model, replicating the structural properties of the D1NAMO and HUPA-UCM collections; validation on the original clinical recordings is planned. Among the two synthetic datasets, the D1NAMO-equivalent cohort (nine patients) proves more challenging, with systematically higher per-patient RMSE variance. The clinically acceptable prediction accuracy at the 30 min horizon (99.7% in Clarke zones A + B) suggests potential for integration into insulin dosing decision-support systems. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disorder linked to obesity, insulin resistance, and dyslipidemia. Nutrition plays a central role in modulating hepatic lipid metabolism, oxidative stress, and inflammation, yet practical, evidence-based dietary strategies remain limited. This study aimed to develop Mediterranean diet-based meal plans with varying macronutrient compositions and to characterize their nutritional profiles, as well as to evaluate them using established nutritional indices and diet score calculations, such as the Dietary Inflammatory Index, Dietary Antioxidant Index, and dietary lipid indices. Methods: Clinical practice guidelines (CPGs) from various academic and professional organizations were reviewed to assess current non-pharmacological treatments for MASLD, with a focus on determining whether the Mediterranean diet is the most recommended dietary pattern. Traditional, low-carbohydrate, and low-fat MedDiet patterns were translated into food-based meal plans. A 7-day meal plan was developed and analyzed for nutrient composition, then evaluated using the Dietary Inflammatory Index (DII), Dietary Antioxidant Index (DAI), Dietary Lipophilic Index (DLI), and Dietary Lipophilic Load (DLL). A Western diet (WD) that is characterized by ultra-processed food (UPF) was included as a comparative reference. Results: The validated dietary score calculations showed that all MedDiet patterns demonstrated consistently low DII scores (−2.00 to −2.81) and high DAI scores (3 to 20.03), whereas the WD showed high DII scores (5.0 to 6.09) and low DAI scores (−12.47 to −17.99). Despite these variations in macronutrients, the menu developed in the study on three MedDiet patterns showed negative DII and positive DAI scores. When comparing the traditional MedDiet with the WD, which have similar macronutrient distributions, the WD was characterized by less favorable DII and DAI scores. Conclusions: This study provides a descriptive, guideline-informed framework for Mediterranean diet-based meal plans with varying macronutrient compositions. Utilizing DII, DAI, DLI, and DLL offers a potential framework for designing dietary interventions. Further validation through clinical studies is needed to justify the potential for practical and digital translation. Nevertheless, the study provides initial insights that may inform future research on nutritional approaches for MASLD integrating dietary indices. Full article

Lamellar ichthyosis is a rare congenital disorder of keratinization frequently associated with ocular complications, most commonly cicatricial ectropion and exposure keratopathy. We present a case of severe mixed exposure-related and neurotrophic keratopathy with marked corneal thinning in a 61-year-old man with genetically confirmed lamellar ichthyosis. At presentation, the best-corrected visual acuity (BCVA) in the right eye was limited to hand motion (logMAR 2.3). Slit-lamp examination revealed a large central to inferocentral corneal ulcer measuring approximately 3 × 4 mm with severe stromal thinning in the setting of marked lower eyelid ectropion, incomplete eyelid closure, and chronic ocular surface exposure, while anterior segment optical coherence tomography (AS-OCT) demonstrated a minimal corneal thickness of approximately 165 µm. Microbiological swabs obtained from the conjunctival sac were negative, and no purulent discharge, hypopyon, or anterior chamber inflammatory reaction was present, making active infectious keratitis unlikely. Corneal sensitivity measured with Cochet–Bonnet esthesiometry at presentation, centrally and in all four peripheral quadrants of both eyes, was markedly reduced, more severely in the affected right eye, supporting the presence of a severe neurotrophic component contributing to impaired corneal healing. Intensive conservative therapy including preservative-free lubricants, dexpanthenol gel, autologous serum eye drops, topical insulin, prophylactic antibiotics, and systemic doxycycline was initiated. Serial AS-OCT imaging demonstrated progressive structural recovery, with corneal thickness increasing to 438 µm after one month of treatment and complete corneal epithelialization. The BCVA improved to 0.2 Snellen (0.7 logMAR). This case highlights the diagnostic value of multimodal anterior segment imaging in monitoring severe mixed keratopathy with advanced corneal thinning and demonstrates that intensive conservative therapy may stabilize the ocular surface and prevent corneal perforation in patients with lamellar ichthyosis. Full article

Metabolically-dysfunction-associated steatotic liver disease (MASLD) represents the most common chronic liver disease in the pediatric population, and its prevalence has doubled over the past decade. The etiology is multifactorial, including genomic risk factors, perinatal and developmental or behavioral factors. Still, many cases of MASLD are associated with being overweight and obesity, particularly in children who have poor dietary habits and sedentary lifestyles that contribute to excessive weight gain. Given the progressive and heterogeneous nature of MASLD, early identification of high-risk patients before the development of severe liver disease is a major clinical priority. Recent studies indicate that disorders of amino acid metabolism are closely linked to both obesity and MASLD, reflecting profound alterations in systemic metabolic homeostasis. The reported data sustain significant changes in circulating amino acid profiles, particularly elevated levels of branched-chain amino acids (BCAAs) and aromatic amino acids. These alterations are thought to reflect fundamental metabolic disturbances, including insulin resistance, compromised mitochondrial activity, and altered hepatic lipid metabolism. Consequently, alterations in amino acid metabolism have been proposed as potential biomarkers for disease progression and metabolic dysfunction in MASLD. This review aims to evaluate the correlation between the amino acid profile and histological changes in pediatric MASLD, including steatosis, steatohepatitis, and fibrosis. Full article

Background: Screening for presymptomatic type 1 diabetes (T1D) reduces the risk of diabetic ketoacidosis (DKA) and allows for early intervention with disease-modifying therapies. Despite the rising incidence of T1D in Bulgaria, screening initiatives remain limited. This pilot study aims to evaluate the feasibility of selective T1D screening in high-risk children and identify potential clinical associations with islet autoimmunity. Methods: The study targeted a recruitment of 250 children aged 0–18 years (200 with a relative with T1D and 50 without). Screening for islet autoantibodies (AABs), including glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated-2 (IA-2A), zinc transporter-8 (ZnT8A), and islet cell cytoplasmic autoantibodies (ICAs), was performed via chemiluminescence immunoassay (CLIA). Participants testing positive for one or more AABs were scheduled for longitudinal immunological and metabolic follow-up to evaluate the persistence of autoimmunity and disease progression. Results: Between October 2024 and February 2026, the pilot study recruited 210 participants (84% of the 250 target), including 160 children with a relative (target 200) and 50 without a family history of T1D (target 50). Within the high-risk group, seven children (4.4%) tested positive for a single autoantibody (3 GADA, 2 ZnT8A, 1 IA-2A, and 1 IAA), while no autoantibodies were detected in the group without a relative. No cases of multiple autoantibody positivity or stage 3 T1D were identified in either group. Furthermore, no statistically significant associations were observed between autoantibody positivity and secondary factors, including breastfeeding, allergic status, a high-glycemic diet, frequent illness, and personal history of autoimmune disease. Conclusions: The findings validate the feasibility of selective T1D screening in Bulgaria, driven by high public interest and successful recruitment across both high-risk and general population cohorts. While this exploratory study found no significant clinical correlations, it establishes a vital roadmap for larger, longitudinal research. Ultimately, this pilot framework provides a scalable model for implementing standardized early detection to reduce the burden of T1D on the national healthcare system. Full article

Human adipose biology is strongly influenced by three-dimensional (3D) architecture, cell–cell interactions, and local oxygen availability maintained over a long-term culture period, features that are not reproduced in traditional two-dimensional (2D) culture systems. To address this gap, we established a long-term human adipose-derived stem cell (hASC) spheroid model using elastin-like polypeptide–polyethyleneimine (ELP-PEI) coating. The ELP-PEI coating facilitated stable spheroid formation and sustained adipogenic differentiation over 56 days. As spheroids enlarged and matured, they exhibited hallmark features of adipocytes, including lipid accumulation, morphological compaction, and transition out of the proliferative state. Glucose uptake increased during maturation and declined as spheroids became larger. This reduction coincided with a marked rise in hypoxia-inducible factor-1α (HIF-1α) expression, indicating the emergence of a hypoxic microenvironment within larger spheroids. Notably, inhibiting HIF-1α restored insulin-stimulated glucose uptake, demonstrating that hypoxia was the primary driver of impaired insulin responsiveness in late-stage spheroids. These findings position ELP-PEI-supported hASC spheroids as a practical and physiologically relevant platform for studying human adipocyte biology, particularly the development and reversibility of hypoxia-associated metabolic dysfunction. This model offers new opportunities for mechanistic studies and for evaluating therapeutic strategies targeting insulin resistance and adipose tissue pathology. Full article

The reproductive caste of higher termites exhibits remarkable longevity, but the mechanisms by which they manage age-related oxidative stress during lifespan extension remain insufficiently understood. This study investigated the dynamic regulation of the insulin/IGF (IIS)–FOXO axis, a key anti-aging regulatory pathway that integrates insulin signaling with downstream processes, including antioxidant defense and DNA repair, as well as the superoxide dismutase (SOD) system in female Odontotermes formosanus reproductives at various life stages (Swarming Queen (SQ), 1-Year Queen (1YQ), 8-Year Queen (8YQ)) through transcriptomic, qRT-PCR, and enzyme activity analyses. Age-dependent upregulation of IIS pathway components (InR, chico, PDK1, Akt, Sirt1, FOXO) was observed, alongside the identification of six SOD transcripts, including two SOD1, two SOD2, and two SOD3 isoforms. Notably, mitochondrial SOD2 (particularly SOD2_b) showed a progressive increase with age, exhibiting the highest enzymatic activity and being associated with reduced mitochondrial oxidative stress and the disruption of reactive oxygen species (ROS) amplification cycles. These findings suggest that O. formosanus reproductives counteract the potential lifespan-reducing effects of chronic IIS activation by maintaining or enhancing FOXO activity, thereby supporting DNA repair, antioxidant defenses, and cellular homeostasis. The IIS–FOXO–SOD2 axis is identified as a key regulator of reproductive longevity in higher termites, offering new insights into the molecular mechanisms behind lifespan extension in social insects. Full article

Background/Objectives: Vitamin D plays an important role in glucose metabolism, lipid regulation, and inflammatory processes, and has been implicated in cardiometabolic health. However, its associations with specific metabolic biomarkers remain inconsistent, particularly in older adults. This study aimed to examine whether vitamin D deficiency is differentially associated with multiple metabolic biomarkers in a nationally representative sample of older adults. Methods: This cross-sectional study used data from the 2024 Korea National Health and Nutrition Examination Survey, including 1806 adults aged ≥65 years. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D levels < 20 ng/mL. Metabolic biomarkers included fasting glucose, glycated hemoglobin (HbA1c), triglycerides, C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-C), waist circumference, and body mass index (BMI). Complex sample linear regression analyses were performed with sequential adjustment for sociodemographic factors, health behaviors, and comorbidities. Results: In unadjusted analyses, vitamin D deficiency was associated with adverse metabolic profiles, including higher fasting glucose, HbA1c, triglycerides, waist circumference, and CRP levels, and lower HDL-C levels. After adjustment for sociodemographic factors, health behaviors, and comorbidities, significant associations remained for HbA1c (β = 0.10, p = 0.034), triglycerides (β = 0.10, p = 0.003), and waist circumference (β = 1.21, p = 0.040). No significant associations were observed for fasting glucose, HDL-C, CRP, or BMI. Conclusions: Vitamin D deficiency was independently associated with poorer long-term glycemic status, hypertriglyceridemia, and central adiposity in older adults, but not with other metabolic markers after adjustment. These findings suggest that the metabolic correlates of vitamin D deficiency may be domain-specific rather than generalized. Longitudinal and interventional studies are needed to clarify causality and underlying mechanisms. Full article

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article summarizes current evidence to propose that exercise functions as a signaling network regulator, concurrently modulating critical lipid metabolism-related signaling pathways: cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase–protein kinase B (PI3K–AKT), forkhead box O (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways. We delineate how dysregulation of these signaling pathways contributes to lipid disorders in T2DM, highlighting their tissue-specific and often bidirectional roles. Subsequently, we detail the molecular adaptations induced by various exercise modalities—from aerobic training to high-intensity intervals—that restore homeostasis of this signaling network. By integrating these findings, we present a novel framework for precision exercise—defined as the tailoring of exercise modality, intensity, and volume based on an individual’s predominant signaling pathway disturbance, assessed via circulating or tissue-specific biomarkers. This framework advocates for future exercise prescriptions to be guided by molecular profiling alongside traditional physiological indicators. This mechanistic insight not only deepens our comprehension of exercise physiology but also paves the way for more effective, personalized strategies to combat T2DM and its metabolic complications. Full article

Hepatitis C virus (HCV) infection is a global health concern, chronically affecting over 71 million people. It primarily targets the liver but also causes systemic complications through inflammation, oxidative stress, and metabolic dysregulation. HCV is a highly variable RNA virus with six major genotypes that are mainly transmitted via blood. Often asymptomatic, the infection progresses silently to chronic hepatitis C (CHC), which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have revolutionized treatment, achieving cure rates above 95%, improving liver function, reversing fibrosis, and normalizing metabolism. HCV disrupts iron metabolism by suppressing hepcidin, causing iron overload and oxidative stress. It also alters lipid metabolism, inducing steatosis, and affects glucose metabolism, contributing to insulin resistance and type 2 diabetes. DAAs improve these metabolic outcomes. HCV promotes oxidative stress via viral proteins, damaging liver cells and DNA and triggering inflammation and fibrogenesis. Even post-cure, oxidative stress and iron overload may continue to drive disease progression. Genetic and epigenetic factors influence fibrosis progression and HCC risk. Despite a sustained virologic response (SVR), patients with advanced liver damage remain at risk for HCC and metabolic diseases, highlighting the need for continued monitoring and personalized post-treatment care. Full article

The degradation of plastic waste leads to the release of numerous chemical additives, including phthalate plasticizers, which have been implicated in the pathogenesis of metabolic disorders. Di (2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer whose primary metabolite, mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), has been associated with multiple metabolic diseases. In this study, we applied an integrated approach combining network toxicology and molecular docking to systematically investigate the potential mechanistic role of MECPP in metabolic dysregulation. Our strategy included multi-platform target prediction, disease gene association analysis, functional enrichment, protein–protein interaction network construction, and molecular docking analysis. The results suggested that MECPP may be associated with six common core targets, including BCL2, BCL2L1, MAPK14, MMP2, MMP9, and TNFRSF1A, which are mainly involved in apoptosis, inflammatory regulation, and extracellular matrix remodeling. Pathway enrichment analysis further indicated the potential involvement of several disease-overlapping pathways, including insulin resistance, neuroactive ligand–receptor interaction, efferocytosis, advanced glycation end product–receptor for advanced glycation end product (AGE–RAGE) signaling, phospholipase D signaling, and renin secretion. Overall, these findings suggest that MECPP may contribute to metabolic dysregulation through overlapping molecular mechanisms across multiple diseases. This study provides a computational basis for future experimental validation and environmental risk assessment. Full article

Ferroptosis, a type of iron overload-induced cell death, is involved in diabetes-induced testicular dysfunction. Hence, this study was designed to investigate, for the first time, the impact of lipoxin A4 (LXA4) administration on testicular tissue in diabetic rats and explore its probable role in regulating ferroptosis in comparison with the standard ferroptosis inhibitor (ferrostatin-1, Fer-1). Albino rats of Wistar strain were divided into a control group, a type II diabetes mellitus (DM) group, a DM + Fer-1group, and a DM + LXA4 group. Serum levels of iron, insulin, glucose, total cholesterol, triglycerides, and testosterone were assayed. Testicular tissue markers of oxidative stress, ferroptosis, and inflammation were also assessed by different methods. Our results confirmed diabetes-induced testicular injury and disruption of its function via inducement of ferroptosis, but this was ameliorated with LXA4 and Fer-1 administration. However, Fer-1 showed a greater protective effect compared to LXA4 under the conditions of this study. We concluded that LXA4 partially secured the testicular tissue of diabetic rats against ferroptosis via augmenting the antioxidant Nrf2/SLC7A11/GPX4 pathway. Therefore, LXA4 may have a possible protective effect on the testicular tissue of diabetic patients. Full article

Acute liver failure is often accompanied by neurological disturbances collectively referred to as hepatic encephalopathy (HE), characterized by neuroinflammation and subsequent cognitive decline. Insulin-like growth factor 1 (IGF1) is a neuroprotective peptide with anti-inflammatory properties in the brain. The role of IGF1 in cognitive deficits and neuroinflammation during HE remains largely unexplored. In C57Bl/6 mice, HE was established through an intraperitoneal injection of azoxymethane (AOM), and tissues were collected at defined time points during disease development. IGF1 expression in the cortex was downregulated following AOM administration. Central infusion of recombinant mouse IGF1 (rmIGF1) before AOM injection resulted in delayed neurological impairment, reduced microglial activation, and decreased proinflammatory cytokine and chemokine production in AOM mice. In vitro, rmIGF1 and conditioned media derived from rmIGF1-treated primary neurons attenuated phagocytic activity and C–C motif chemokine ligand 2 (CCL2) production in the microglial cell line EOC-20. Collectively, our results show that IGF1, whose levels decline during HE, alleviates neuroinflammation and improves the pathological state of AOM-treated mice through the suppression of microglial activation and the regulation of neuron–microglia paracrine communication. Full article

Background/Objectives: Chronic metabolic acidosis (CMA) is a mild, persistent acid–base imbalance characterized by low serum bicarbonate and urinary pH and is common in chronic illness, aging, and metabolic disorders such as type 2 diabetes (T2D). This review highlights the critical, yet often overlooked, role of CMA in T2D (CMAD) and its contribution to disease pathophysiology. Methods: We conducted a comprehensive review of the systemic impacts of CMA, from molecular mechanisms to organ-specific dysfunction. The analysis covers physiological pH dynamics in intracellular (IC) and extracellular (EC) fluids and explores their effects on cellular processes, including the cell cycle and apoptosis. Results: At the molecular level, acidosis significantly alters enzyme kinetics, macromolecule metabolism, and ion conductance. Cell-level analysis shows that pH shifts impact proliferation and programmed cell death. Systemically, the manifestations of CMA align closely with T2D features in vital organs, including the pancreas, liver, skeletal muscle, adipose tissue, and the renal, nervous, and immune systems. Our findings indicate that the pathophysiological landscape of T2D largely mirrors the biological effects of chronic acidosis. Conclusions: The alignment between the effects of CMA and the clinical features of T2D suggests that T2D pathophysiology is worth revisiting through the lens of CMAD. This perspective is further supported by therapeutic interventions showing preliminary efficacy signals in limited studies of acid-neutralization in managing T2D symptoms and progression. Full article

Background: Noninvasive transdermal insulin delivery using ultrasound technology has gained attention for improving the glycemic control of insulin-dependent patients. Methods: Indirect functional comparison and evaluation of insulin dosage, between noninvasive ultrasound-mediated transdermal delivery and needle injection methods, was achieved utilizing in vivo blood glucose measurements of temporary hyperglycemic rabbits. Nine rabbits were divided into three groups: (i) untreated control, (ii) subcutaneous injection and (iii) ultrasound-mediated transdermal delivery. Animals were anesthetized using a combination of ketamine hydrochloride and sodium xylazine to produce temporary hyperglycemic rabbits during the experiments. The rabbits in the control group did not receive insulin, while the animals in the ultrasound group received insulin transdermally for 10 min utilizing a customized single-element piston-shaped ultrasound transducer operated by multi-frequency electrical signals from 100 to 200 kHz. Rabbits in the direct subcutaneous injection group were anesthetized and injected with 0.25 units/kg of insulin. Results: With an initial blood glucose baseline level of 228.7 ± 13.1 (mg/dL) for all rabbits, the in vivo results of control group showed an increase above the baseline by 129.7 ± 27.3 (mg/dL) at the end of the in vivo experimental period (80 min). However, the ultrasound-mediated delivery and subcutaneous injection groups showed noticeable statistically significant percentage reductions in blood glucose levels by 43.9 ± 5.4 and 42.7 ± 6.6, respectively, compared to the control group by the end of the in vivo experiments. Conclusions: In vivo glucose response results confirmed that piston-shaped ultrasound transducers achieved indirectly similar insulin dosage delivery by ultrasound energy for tested animals with no statistically significant differences once compared to the results of the subcutaneous needle injection group. Full article